Calcium Chloride for Prevention of Blood Loss During Intrapartum Cesarean Delivery (CALBLOC)

Calcium Chloride for Prevention of Blood Loss From Uterine Atony During Intrapartum Cesarean Delivery (CALBLOC): a Double Blind, Randomized, Placebo Controlled Trial and Nested Population Pharmacokinetic and Pharmacodynamic Analysis

Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. Up to 80% of PPH is caused by uterine atony, the failure of the uterine smooth muscle to contract and compress the uterine vasculature after delivery. Laboratory and epidemiological studies show that low extracellular and serum calcium levels, respectively, decrease uterine contractility. A pilot study performed by the investigators supports the hypothesis that intravenous calcium chloride is well tolerated and may have utility in preventing uterine atony. The proposed research will establish the relationship between uterine tone and calcium through a clinical trial with an incorporated pharmacokinetic and pharmacodynamic (PK/PD) study. In a randomized, placebo-controlled, double-blind trial, investigators will establish the effect of 1 gram of intravenous calcium chloride upon quantitative blood loss and uterine tone during cesarean delivery in parturients with high risk of uterine atony. Investigators will concurrently collect serial venous blood samples to measure calcium for PK/PD modeling in this pregnant study cohort. High-quality clinical research and development of novel therapeutics to manage uterine atony are critical to reduce the high maternal morbidity and mortality from PPH.

Study Overview

• Status: Completed
• Conditions: Cesarean Section Complications; Postpartum Hemorrhage; Uterine Atony; Uterine Atony With Hemorrhage
• Intervention / Treatment: Drug: Calcium chloride; Drug: Saline placebo

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Pacifica, California, United States, 94044
      • Jessica Ansari

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient had a trial of labor for vaginal delivery prior to cesarean
• Patient received an oxytocin infusion for labor augmentation or induction prior to cesarean

Exclusion Criteria:

• renal dysfunction with serum Cr >1.0 mg/dL
• known underlying cardiac condition
• treatment with digoxin within the last 2 weeks for a maternal or fetal indication
• treatment with a calcium channel blocker medication within 24 hours
• hypertension necessitating intravenous antihypertensive medication within 24 hours
• emergent case in which study participation could in any way impede patient care by the judgement of the obstetrician, anesthesiologist, or bedside nurse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Calcium chloride; 1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery.	Drug: Calcium chloride; See arm description above
Placebo Comparator: Saline placebo; 60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery.	Drug: Saline placebo; see arm description above

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Blood Loss	Standardized volumetric and gravimetric assessment of blood loss during cesarean. Note: will analyze all participants, but planned subgroup analysis will also occur excluding patients with non-atonic reasons for blood loss including hysterotomy extension, placental abruption, cervical or vaginal laceration, etc	measurement occurs at conclusion of operating room case

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Postpartum Hemorrhage	Postpartum hemorrhage was defined as quantitative blood loss > 1000 milliliters during operative course	operative course (within 4-6 hours of fetal delivery)
Number of Participants With Second Line Uterotonic Requirement	Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony	within 4 hours of delivery
Number of Patients With a Transfusion Requirement	Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge	96 hours of delivery
Change in Hematocrit From Baseline	Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused	1 day
Total Oxytocin Bolus Requirement	Total dose oxytocin bolus during cesarean	Cesarean duration, within 4-6 hours of fetal delivery
Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery	Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, 2021). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus.	7 minutes after fetal delivery, 5 minutes after initiating study drug infusion
Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery	Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, PMID 33652161). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus.	12 minutes after fetal delivery, 10 minutes after initiating study drug infusion
Fluid Requirement	Total crystalloid required during cesarean delivery in mL	Operating room duration, usually 2 hours
Percent Change in Mean Arterial Pressure	Baseline mean arterial blood pressure recorded as average of first 6 mean arterial blood pressures recorded in operating room. Percent change calculated as measured mean arterial blood pressure minus baseline, divided by baseline. Reported here as the maximal decrease in mean arterial pressure. Repeated measures ANOVA reported in Statistical Analysis.	every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline
Percent Change in Heart Rate From Baseline	Baseline heart rate recorded as average of first 6 heart rates recorded in operating room. Percent change calculated as measured heart rate minus baseline, divided by baseline. Maximal % increase in heart rate reported here. Repeated measures ANOVA used to analyze overall trend in Statistical Analysis below.	every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline
Total Phenylephrine Requirement	Total phenylephrine in milligrams administered while in the operating room	Duration of operating room time, up to 240 minutes
Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium	Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels	In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration)
Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride	Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations.	At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion
Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS	Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done.	Within 20 minutes of study drug administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding	Pre-specified subgroup analysis of primary outcome: Because the proposed mechanism of calcium action-improving uterine contractility-was not expected to improve bleeding from causes such as hysterotomy extension or arterial bleeding, the trial was powered for a prespecified subgroup analysis excluding patients with nonatonic blood loss documented in the surgeon's operative report. Documented nonatonic bleeding was defined as presence in the surgeon's operative report narrative of any of the following: hysterotomy extension, hysterotomy types other than low transverse (eg classical, T- or J-shaped), invasive or abnormally adherent placenta, placental abruption, uterine rupture, bleeding from leiomyomas, grade 3 or 4 vaginal lacerations, or cervical lacerations.	Calculated at conclusion of operating room case

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Foundation for Anesthesia Education and Research; Society for Obstetric Anesthesia and Perinatology
• Investigators: Principal Investigator: Jessica Ansari, MD, Stanford University

Publications and helpful links

General Publications

• Cole NM, Abushoshah I, Fields KG, Carusi DA, Robinson JN, Bateman BT, Farber MK. The interrater reliability and agreement of a 0 to 10 uterine tone score in cesarean delivery. Am J Obstet Gynecol MFM. 2021 May;3(3):100342. doi: 10.1016/j.ajogmf.2021.100342. Epub 2021 Feb 27. Erratum In: Am J Obstet Gynecol MFM. 2022 Mar;4(2):100536.
• Ansari JR, Yarmosh A, Michel G, Lyell D, Hedlin H, Cornfield DN, Carvalho B, Bateman BT. Intravenous Calcium to Decrease Blood Loss During Intrapartum Cesarean Delivery: A Randomized Controlled Trial. Obstet Gynecol. 2024 Jan 1;143(1):104-112. doi: 10.1097/AOG.0000000000005441. Epub 2023 Nov 3.

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2022
• Primary Completion (Actual): March 29, 2023
• Study Completion (Actual): April 3, 2023

Study Registration Dates

• First Submitted: August 18, 2021
• First Submitted That Met QC Criteria: August 25, 2021
• First Posted (Actual): August 30, 2021

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: May 20, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: uterine atony; postpartum hemorrhage; cesarean delivery; calcium chloride; intrapartum cesarean
• Additional Relevant MeSH Terms: Pathologic Processes; Pregnancy Complications; Obstetric Labor Complications; Puerperal Disorders; Uterine Hemorrhage; Dystocia; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hemorrhage; Postpartum Hemorrhage; Uterine Inertia; Physiological Effects of Drugs; Calcium-Regulating Hormones and Agents; Calcium
• Other Study ID Numbers: 62206; MRTG-02-15-2022-Ansari (Other Grant/Funding Number: Foundation for Anesthesia Education and Research); YIG-2020 (Other Grant/Funding Number: Society Obstetric Anesthesia and Perinatology)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No